tbuckley/cabot-search huggingface dataset:
Intratumoral administration of STING-activating nanovaccine enhances T cell immunotherapy
Authors: Xiaoyi Jiang, Jian Wang, Xichen Zheng, Zhida Liu, Xinyu Zhang, Yuwei Li, Jonathan Wilhelm, Jun Cao, Gang Huang, Jinlan Zhang, Baran Sumer, Jayanthi Lea, Zhigang Lu, Jinming Gao, Min Luo
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Cancer vaccines are able to achieve tumor-specific immune editing in early-phase clinical trials. However, the infiltration of cytotoxic T cells into immune-deserted tumors is still a major limiting factor. An optimized vaccine approach to induce antigen-specific T cells that can perform robust tumor infiltration is important to accelerate their clinical translation. We previously developed a STING-activating PC7A nanovaccine that produces a strong anti-tumor T cell response on subcutaneous injection. This study systematically investigated the impact of administration methods on the performance of nanovaccines. Methods Tumor growth inhibition by intratumoral delivery and subcutaneous delivery of nanovaccine was investigated in TC-1 human papillomavirus-induced cancer model and B16-OVA melanoma model. Nanovaccine distribution in vivo was detected by clinical camera imaging, systemic T cell activation and tumor infiltration were tested by in vivo cytotoxicity killing assay and flow cytometry. For mechanism analysis, T cell recruitment was investigated by in vivo migration blocking assay, multiplex chemokine array, flow cytometry, RT-qPCR, chemotaxis assay and gene knockout mice. Results Nanovaccine administration was found to alter T cell production and infiltration in tumors. Intratumoral delivery of nanovaccines displayed superior antitumor effects in multiple tumor models compared with subcutaneous delivery. Mechanistic investigation revealed that intratumoral administration of the nanovaccine significantly increased the infiltration of antigen-specific T cells in TC-1 tumors, despite the lower systemic levels of T cells compared with subcutaneous injection. The inhibition of tumor growth by nanovaccines is primarily dependent on CD8 + cytotoxic T cells. Nanovaccine accumulation in tumors upregulates CXCL9 expression in myeloid cells in a STING dependent manner, leading to increased recruitment of IFNγ-expressing CD8 + T cells from the periphery, and IFNγ reciprocally stimulates CXCL9 expression in myeloid cells, resulting in positive feedback between myeloid-CXCL9 and T cell-IFNγ to promote T cell recruitment. However, the STING agonist alone could not sustain this effect in the presence of a systemic deficiency in antigen-specific T cells. Conclusions Our results demonstrate that intratumoral administration of PC7A nanovaccine achieved stronger antitumor immunity and efficacy over subcutaneous injection. These data suggest intratumoral administration should be included in the therapeutic design in the clinical use of nanovaccine.
MEDB-86. A re-induction regimen for children with recurrent medulloblastoma
Authors: Katrina O'Halloran, Sheetal Phadnis, Laura Metrock, Gregory Friedman, Tom Davidson, Nathan Robison, Girish Dhall, Ashley Margol
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma is the most common malignant brain tumor of childhood. Despite multi-modal therapies, ~30% of patients experience disease recurrence, which portends a poor prognosis. At initial recurrence, intensive chemotherapy may be effective prior to various consolidation therapies including high dose chemotherapy with autologous stem cell rescue or irradiation. We report outcomes for nine children treated at two institutions with the following regimen: cyclophosphamide 1500mg/m2/dose days 1,2; irinotecan 125mg/m2/dose days 1,8; temozolomide 150mg/m2/dose days 1-5, and oral etoposide 50mg/m2/dose days 1-7. Patients received 2-4 cycles based upon disease response and physician preference. The mean time from initial diagnosis to first recurrence was 19 months. After receiving two cycles of therapy, two patients had complete response (CR) and proceeded to consolidation. Of the remaining seven patients, five had partial response (PR) and two had stable disease (SD). Overall response rate was 78% after 2 cycles. Two patients with PR proceeded directly to consolidation with irradiation. Five patients (3 PR, 2 SD) received 2 additional cycles. After four cycles there was one CR, two with minimal residual disease, one SD and one progressive disease (PD). Four patients (44%) are alive with no evidence of disease (NED). One patient died of consolidation-related toxicity but had NED at time of death 28 months from initial recurrence. Five patients developed PD. Two patients died of disease, two are alive with disease, and one is alive with NED after PD and additional therapy. There were no treatment-related deaths. Infection was the most common complication. Five patients had febrile neutropenia and two developed sepsis. One patient required dose reduction for prolonged thrombocytopenia. Peripheral blood stem cell collection was achieved in all patients for whom it was attempted. This re-induction regimen is generally well-tolerated and effective in inducing responses for children with recurrent medulloblastoma.
Renal scintigram assessment of the residual renal function following partial neprectomy and embolization of postoperative pseudoaneurysm or arteriovenous fistula: A single center series
Authors: G. Novara, V. Lami, J. Collavino, G. Zecchini, L. Evangelista, P. Bartoletti, G. De Conti, A. Morlacco, G. Betto, N. Zanovello, F. Dal Moro
Journal: European Urology (2022)
A randomized, open-label, crossover study assessing the pharmacokinetic and pharmacodynamic bioequivalence of pegfilgrastim-cbqv via on-body injector vs prefilled syringe.
Authors: Hong Tang, Francesca Civoli, Suzanna Tatarewicz, Lisa Miyasaki, Hillary O'Kelly, Alasdair Young, Barbara Finck
Journal: Journal of Clinical Oncology (2022)

e18637 Background: Pegfilgrastim-cbqv, a pegfilgrastim biosimilar, is administered 24-72 h after myelosuppressive chemotherapy to prevent febrile neutropenia. Pegfilgrastim delivery via an on-body injector (OBI) applied on the day of chemotherapy eliminates the need for a second healthcare visit. This study evaluated the pharmacokinetic (PK), pharmacodynamic (PD) bioequivalence (BE), and the safety of pegfilgrastim-cbqv administered via OBI vs prefilled syringe. Methods: In this open-label, 2-period crossover study, healthy adult male participants were randomized 1:1 to 2 treatment sequences to receive a 6-mg subcutaneous (SC) injection of pegfilgrastim-cbqv via OBI or prefilled syringe in period 1 and an injection via the other method in period 2 (after a 6- to 8-wk washout). Primary endpoints (PK) were area under the concentration-time curve from time 0 to infinity (AUC 0-inf ), the AUC from time 0 to the last quantifiable concentration (AUC 0-last ), and the maximum plasma concentration (C max ). Secondary endpoints (PD) were area under the absolute neutrophil count (ANC)-time curve from time 0 to the last quantifiable ANC (ANC AUC 0-last ) and maximum ANC (ANC max ). PK/PD BE was established if the 90% CI for the geometric mean ratios (GMRs) fell within 80-125%. Safety and immunogenicity were also assessed. Results: The 90% CIs of the GMRs for PK and PD endpoints in healthy participants fell within the predetermined range (Table). Treatment-emergent adverse events (TEAEs) occurred in 87.8% (OBI) vs 75.8% (prefilled syringe) of participants. Most TEAEs were musculoskeletal effects and mild in severity. The most common injection siterelated TEAE was erythema (OBI 34.1%; prefilled syringe 2.5%). The injection site erythema reactions were mild in severity and self-limiting. The incidence of treatment-emergent antidrug antibodies (ADAs) in period 1 was similar with OBI (40.0%) vs prefilled syringe (36.6%); ADA titers were low, transient, and primarily directed to the polyethylene glycol (PEG) moiety of pegfilgrastim-cbqv. The ADAs had no apparent impact on PK, PD, or safety. Neutralizing antibodies were not detected in any participant. Conclusions: This study demonstrated PK and PD BE of pegfilgrastim-cbqv administered via OBI vs prefilled syringe in healthy adult males. OBI and prefilled syringe administration had similar safety and immunogenicity profiles. No unexpected safety signals were identified.[Table: see text]
Is the Urethral stricture score (U-score) a valid prognosticator in low complexity anterior urethral strictures? Making the case for further granular intraoperative stricture assessment
Authors: M.W. Vetterlein, B. Kranzbühler, L. Ding, L.A. Kluth, L. Kühnke, F. König, A. Soave, M. Fisch, R. Dahlem, P. Marks
Journal: European Urology (2022)
Interactions Between Natural Selection and Recombination Shape the Genomic Landscape of Introgression
Authors: Maud Duranton, John E Pool
Journal: Molecular Biology and Evolution (2022)

Abstract Hybridization between lineages that have not reached complete reproductive isolation appears more and more like a common phenomenon. Indeed, speciation genomic studies have now extensively shown that many species’ genomes have hybrid ancestry. However, genomic patterns of introgression are often heterogeneous across the genome. In many organisms, a positive correlation between introgression levels and recombination rate has been observed. It is usually explained by the purging of deleterious introgressed material due to incompatibilities. However, the opposite relationship was observed in a North American population of Drosophila melanogaster with admixed European and African ancestry. In order to explore how directional and epistatic selection can impact the relationship between introgression and recombination, we performed forward simulations of whole D. melanogaster genomes reflecting the North American population’s history. Our results revealed that the simplest models of positive selection often yield negative correlations between introgression and recombination such as the one observed in D. melanogaster. We also confirmed that incompatibilities tend to produce positive introgression–recombination correlations. And yet, we identify parameter space under each model where the predicted correlation is reversed. These findings deepen our understanding of the evolutionary forces that may shape patterns of ancestry across genomes, and they strengthen the foundation for future studies aimed at estimating genome-wide parameters of selection in admixed populations.
An investigator-initiated phase II trial of a PARP inhibitor niraparib monotherapy for patients with pre-treated, <i>BRCA</i>-mutated, unresectable/recurrent biliary tract, pancreatic, and other gastrointestinal cancers (NIR-B trial).
Authors: Yasuyuki Kawamoto, Chigusa Morizane, Yoshito Komatsu, Makoto Ueno, Masafumi Ikeda, Masayuki Furukawa, Taroh Satoh, Yutaka Hatanaka, Isao Yokota, Yoshiaki Nakamura, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2022)

TPS4174 Background: Recent comprehensive genomic profiling tests have revealed therapeutic target molecules. However, because many targets are present in only a small fraction of patients, a large number of patients need to be screened for enrollment in a single study. In order to overcome this patient identification barrier, the SCRUM-Japan, nationwide large-scale genomic profiling platform, efficiently has been performed umbrella- and basket-type clinical trials. Among the platforms, we have reported that there are BRCA1/2-mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is an anticancer drug belonging to poly(ADP-ribose) polymerase (PARP) inhibitors. Niraparib has been shown to be selective for PARP1/2, to be more cytotoxic among other PARP inhibitor because of its PARP trapping activity. Methods: This is an investigator-initiated, multicenter, three-cohort phase 2 study. Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (cohort A), pancreatic cancers (cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Primary endpoint is the investigator-assessed objective response rate in each cohort with a threshold-response rate of 10% and an expected response rate of 35%. Key secondary endpoints are progression-free survival, overall survival, disease control rate, duration of response, and safety. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL receive 200 mg of niraparib, orally once daily. Furthermore, pre-treatment tumor tissue and serial ctDNA will be collected and analyzed to investigate the resistance mechanisms and provide clinically meaningful biomarker which may be used for identifying and implementing treatment changes. The trial was initiated in January 2021 with enrollment being ongoing. Thirty-three out of planned 60 patients (cohort A/B/C; 25/25/10, respectively) have been enrolled as of December 2021. Funding: Takeda Pharmaceutical Co., Ltd. Clinical trial information: jRCT2011200023.
Characteristics of expression of cancer stem cell markers in various approaches to cervical cancer treatment.
Authors: Anna P. Menshenina, Elena P. Ulianova, Evgeniya M. Nepomnyashchaya, Aleksandr B. Sagakyants, Ekaterina V. Verenikina, Tatiana I. Moiseenko, Elena M. Frantsiyants, Anna A. Cherkasova, Olga G. Selezneva, Mark A. Rogozin
Journal: Journal of Clinical Oncology (2022)

e17516 Background: Cancer stem cells (CSCs) are being actively studied as a possible origin of malignant neoplasms. Research of the properties of CSCs and mechanisms of their regulation holds the promise of the development of new approaches to antitumor therapy. The most frequently detected CSC markers in different tumors are CD44 and CD133. In this regard, the aim of our study was to identify characteristics of expression of CSC markers in cervical cancer treatment and their possible predictive value. Methods: The study included 237 patients with locally advanced cervical cancer T2a-2bNx-1M0. Patients were divided depending on the treatment: neoadjuvant chemotherapy with cisplatin and bleomycin (NACT, n = 84); plasmapheresis (PA) in combination with NACT (PA+NACT, n = 60); PA+NACT with nonspecific immunotherapy with an interferon inducer (PA+NACT+IT, n = 93). Immunohistochemical study was performed on sections from paraffin blocks of tumors using anti-CD44 monoclonal mouse antibodies (156-3C11, Thermo Scientific) at a dilution of 1:2500 and anti-CD133 polyclonal rabbit antibodies (AF5120, Affinity Biosciences) at a dilution of 1:400 (Thermo autostainer Scientific 480S). Membrane staining and staining intensity were evaluated: 0, 1+ weak, 2+ moderate, 3+ strong staining. Protein expression was defined as positive when staining was detected in ≥10% of all tumor cells with a staining intensity ≥2. Statistical analysis of the results was performed with the STATISTICA 13.0 program (StatSoftInc., USA) using the Mann-Whitney U-test. Results: Tumors with positive CD133 and CD44 expression were observed in all groups of patients. However, only PA+NACT+IT patients had CD133- (57%) and CD44- (43%) tumors. Median expression of CD133: in NACT - 70 [60;80]; PA+NACT - 60 [37;70], PA+NACT+IT - 25 [5;60]. Median expression of CD44: in NACT - 30 [10;40]; PA+NACT - 30 [13;65], PA+NACT+IT - 20 [2; 40]. CD133 expression in PA+NACT+IT patients was significantly lower than in PA+NACT and NACT patients by 2.4 times (*p = 0.009) and 2.8 times (*p = 0.002), respectively. CD44 expression in tumors of patients with PA+NACT+IT was 1.5 times lower (statistically non-significant). Differences in tumors of NACT and PA+NACT patients were not found. Conclusions: The immunohistochemical study revealed a decline in the expression of CSC markers (CD133 and CD44) in tumors of patients who received PA+NAPCT+IT. The results obtained for the CD133 marker show its possible value as a predictive factor in the treatment of cervical cancer.
Evaluation of a three-part equity intervention for women of color with breast cancer.
Authors: Jamil Rivers, Evelyn Robles-Rodríguez
Journal: Journal of Clinical Oncology (2022)

TPS1129 Background: Women of color (WOC) with breast cancer miss and fail key points in care due to racial disparities in cancer services. Conscious and unconscious bias means that these women are not treated in a timely way or as rigorously. They are offered fewer options, and the patient navigation and education needed for them to self-advocate is ignored. Black women in particular have the highest breast cancer death rates. Care delivery differs even independent of such variables as literacy, income, and education. Separately and incrementally, findings to date have shown the potential oof patient navigation, equity assessment, and mobile support to reverse these disparities. In pilot investigations –– partnering with academic cancer centers –– The Chrysalis Initiative (a nonprofit patient advocacy and research organization) has validated the potential of combining these approaches in a three-part intervention. Based on preliminary work, it is hypothesized patients will: experience significantly greater adherence to the recommended continuum of care, without disruption or barriers; more often seek second opinions and additional supportive resources, and engage in clinical trials; demonstrate less co-morbidities, through more preventive measures and healthful lifestyle; suffer fewer interactions perceived to be influenced by racism; undergo less financial distress, with guidance on managing and planning costs; feel more confident and more optimistic in their outlook; and achieve better clinical results and lower costs. Methods: To determine and document the full impact, both quantitatively and qualitatively, of the experimental three-part intervention, the trial is: delivering navigation/coaching services to the study population, using counselors who are predominantly WOC who have experienced the challenges of breast cancer care. Surveys and interviews pre- and post-intervention will add to impact measures; providing the experimental group with the BC Navi App on both iOS and Android devices . Developed in partnership with InTouch, the app supports engagement and tracking. It provides a dashboard for care evaluation to supplement EMR data; conducting an equity assessment of breast cancer services of partnering clinical programs through use of focus groups with staff, patients, and community; procedural checks; and data collection from center EHR systems. The review audits 40 domains of care based on NCCI, NCI, ASCO, ACR, and other standards. The assessment team works closely and collaboratively with each cancer center’s clinical and administrative staff to reveal disparities and find consensus on ways to close gaps. This trial in progress is randomizing 200 subjects to the coaching/mobile app intervention arm and 100 to benefits of the equity assessment only, with comparison to nonWOC with breast cancer. The trial aims to disseminate the three-part intervention in easily reproducible form.
A phase II, single-arm, open label, Simon two-stage study of pembrolizumab in patients with metastatic HER2-negative breast cancer: Evaluation of impact of germline variants in APOBEC3B (AUROR).
Authors: Gwo Fuang Ho, Soo-Chin Lee, Joanna Lim, Anita Zarina Bustam, Siew Eng Lim, Marniza Saad, Samuel Guan Wei Ow, Natalie Ngoi, Nur Fadhlina Abdul Satar, Rozita Abdul Malik, Adlinda Alip, Kian Boon Law, Yok Yong Toh, Jia Wern Pan, Soo Hwang Teo
Journal: Journal of Clinical Oncology (2022)

1026 Background: A germline deletion in the APOBEC3B cytosine deaminase gene [A3Bdel] occurs more frequently in Asian women (45% heterozygous deletion (hetD) and 15% homozygous deletion (homD)) compared to in Caucasian women (15% hetD and 4% homD). Carriers are more likely to develop breast cancer, and cancers in carriers are more likely to have a hypermutator phenotype (with C &gt; T transitions) and to be immune-enriched. In this clinical trial, we aim to evaluate whether the immune activation increases response to checkpoint immunotherapy. Methods: In this open label, single arm Phase II study of single agent pembrolizumab in metastatic HER2-receptor negative breast cancer patients with germline deletion in A3B, 40 evaluable subjects who have received &gt; = 1 but &lt; = 3 lines of therapy in a metastatic setting will be enrolled and given pembrolizumab 200 mg intravenously (IV) every 3 weeks (Q3W) for up to 35 administrations (2 years), with Objective Response Rate (ORR) using RECIST 1.1 as the primary study endpoint. The study applies a Simon two-stage design, where if at least 3 out of 22 evaluable patients achieve CR/PR in stage I, the study will proceed to stage II. Results: To date, 84 breast cancer patients were screened for germline A3Bdel, of whom 46 (54.8%) were heterozygous carriers and 12 (14.3%) were homozygous carriers. The study enrolled 22 female A3Bdel carriers with a median age of 59.4 years (range: 32.1, 82.9 years) between September 2020 and September 2021 for stage I analysis. On average, patients received 2 prior lines of chemotherapy in a metastatic setting [6 with 1, 8 with 2 and 8 with 3 lines of prior chemotherapy]. Complete response (CR) was observed in one patient, while partial response (PR) was observed in 4 patients, with an ORR of 22.7% (5 over 22 subjects) in stage I, meeting the pre-defined criteria to proceed to stage II. Notably, the patient with complete response had received 2 prior lines of chemotherapy, whereas of the patients with partial response, 1 had received 1 prior line and 3 had received 3 prior lines of chemotherapy in a metastatic setting. As the observed ORR was greater than the value of r 1 (13.6%), the study has met the statistical criteria to proceed to the stage II enrolment with an additional 18 patients required to complete the entire study. Conclusions: Single agent pembrolizumab demonstrates promising efficacy in germline A3Bdel carriers, who constitute almost two-thirds of Asian patients. Clinical trial information: NCT03989089.